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Amino monothio acids in solid-phase synthesis of peptide thioamides
T Hoeg-Jensen1, A F Spatola, A Holm
1Chemistry Department, Royal Veterinary and Agricultural University, Frederiksberg, Denmark.
International Journal of Peptide and Protein Research
|March 1, 1996
Summary
Researchers developed a novel solid-phase synthesis for thiopeptides using thioacylation. This method efficiently creates endothiopeptides, including analogs of biologically active peptides like thyrotropin-releasing hormone (TRH).
Area of Science:
- Medicinal Chemistry
- Peptide Synthesis
- Organic Chemistry
Background:
- Thioamides in peptide backbones (endothiopeptides) offer unique structural and functional properties.
- Traditional methods for synthesizing endothiopeptides often involve harsh reagents unsuitable for sensitive amino acid side chains.
Purpose of the Study:
- To develop a novel, mild solid-phase synthesis for endothiopeptides.
- To demonstrate the applicability of this method to biologically relevant peptide analogs.
Main Methods:
- Solid-phase thioacylation using N-protected amino monothio acids activated with 6-nitrobenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyNOP).
- Synthesis of endothio analogs of thyrotropin-releasing hormone (TRH) and Leu-Gln-psi[CSNH]-Leu-Lys.
- Characterization using proton and carbon NMR spectroscopy.
- Evaluation of allyl protecting group compatibility and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a deprotection reagent.
Main Results:
- Successful synthesis of endothiopeptides via solid-phase thioacylation, avoiding harsh O/S-exchange reagents.
- Demonstrated synthesis of TRH and Leu-Gln-psi[CSNH]-Leu-Lys analogs, confirming suitability for amino acids with side-chain amides.
- NMR analysis confirmed the thioamide's position in the TRH analog.
- Endothiopeptides are compatible with allyl protecting groups, with DBU showing promise as a piperidine substitute.
Conclusions:
- A novel and efficient solid-phase thioacylation method for synthesizing endothiopeptides has been established.
- This method is versatile and compatible with various amino acids, including those with amide side chains.
- The developed technique facilitates the creation of modified peptides with potential therapeutic applications.